Medical devices for dispensing powders

ABSTRACT

A medical device for topical, intranasal or oral administration of dry powder medical compositions includes a unit dose blister form containing an internal piercing device that provides for agitation, dispersion and dispensation of the powder to a user.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of priority to U.S. ProvisionalApplication 61/472,341 filed Apr. 6, 2011, the disclosure of which isincorporated herein by reference for all purposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not Applicable

REFERENCE TO SEQUENCE LISTING, A TABLE, OR A COMPUTER PROGRAM LISTINGCOMPACT DISK APPENDIX

Not Applicable

FIELD OF THE INVENTION

The present invention is in the technical field of medical devices. Moreparticularly, the present invention is in the technical field of medicaldevices for the administration of drugs, medical compounds, andpharmaceuticals as powders orally or intra-nasally to a user.

BACKGROUND OF THE INVENTION

Certain diseases and medical conditions that are either systemic orlocal to the respiratory tract are treatable via the administration ofdrugs and therapeutic agents taken orally or nasally. There are agrowing number of drugs that are most effectively manufactured, stored,delivered, and administered as a dry powder formulation. A number ofpharmaceutical agents are deliverable as powders or particles orally orintranasally, including but not limited to antibiotics, antipyretics,anti-inflammatories, biologics, vitamins, botanicals, co-factors,enzymes, inhibitors, activators, nutrients, vaccines including DNA basedkilled or live virus or microorganisms, nucleic acids, proteins,peptides, antibodies, peptide mimetics, prophylactic or therapeuticanti-viral and anti-bacterial compounds and biologics, and other agentsor pharmaceutical compositions.

Solid formulated pharmaceuticals have a number of recognized advantages.Compound stability for certain agents is greater in solid formespecially polypeptide and protein based biologics whose conformationaland higher structure may tend to degrade or denature when in solutionthus affecting their biological activity. Similarly, certain drugchemical compounds may tend to dissociate and degrade due to incrementalpH shifts, Van der Waals and other forces resulting in diminished shelflife and drug efficacy. Consequently, unstable drug compounds formulatedas liquids must be refrigerated or even frozen to preserve theireffectiveness which adds cost and complicates deployment. This isespecially troublesome in such cases whereby vaccines and other unstabledrugs are needed to be distributed to remote areas and underdevelopedregions. Often unstable drugs must then be shipped in solid form andreconstituted back to liquid form at the time of administration thusadding expense and the need for skilled personnel for properutilization.

In certain other cases medications are designed in solid form tofacilitate controlled release to result in sustained pharmacologicalconcentrations of active ingredients over an extended period of time.For systemic treatments, powder based drugs delivered eitherintranasally or orally offer a number of advantages including rapid druguptake due to large area pulmonary deposition, the avoidance of theharsh environment of the stomach and intestinal tract as in the case ofpills, tablets, and capsules, and the avoidance of broad systemic andside effects often associated with parenterally administered drugs.Other advantages include enhanced bioavailability, reduced dose volume,and improved patient compliance and ease of self-administration.

Typically these agents and medicaments are formulated and prepared fromsolution by recrystallization followed by milling, but for improvedcontrol over particle crystallinity, shape, mean size, and sizedistribution; lyophilization or various spray drying techniques know inthe art are relied upon to produce a bulk powder with precisecharacteristics to aid in administration. Key characteristics includeprimarily the mean particle size as well as the distribution of sizeswithin the bulk powder. For a given inspiratory velocity initiatedeither nasally or orally, a certain mean particle size and mass isrequired to result in deposition to the targeted tissue location withinthe targeted area within the respiratory tract. Generally, smallerparticles will tend to deposit deeper in the respiratory tract, moreparticularly; particles of 3 or fewer microns in diameter have a greaterprobability to reach the tissues of the lower lungs, with even smalleraerodynamic diameters preferred for enhanced systemic uptake.Conversely, larger particles of greater than 5 microns to the tens ofmicrons or larger, owing to their larger mass are more likely to depositproximally to the point of administration; most typically within thenasal cavity and passages when administered intranasally, or in the oralcavity or pharynx, larynx, or trachea if orally administered. Thedispersity or polydispersity index describes the range and proportion ofsizes within the bulk powder. Depending upon the targeted applicationlocation, a less disperse or mono-disperse powder may be desired toassure a specific deposition location or a more disperse powder may benecessary in order to impact a larger range of tissues such as the casewith certain anti-viral therapies and vaccines where the intent is tocontact the virus residing in several tissue areas and locations withthe respiratory tract. Other aspects of powder engineering are intendedto impact the flowability and reduce the aggregation of the powders inorder to aid in the friability of the material to increase the deliveryefficiency, efficacy and rate of uptake. For that reason, certainexcipients, carriers, or other matrix components may be added in definedquantity to the active dry pharmaceutical agent to impact particleshape, texture and surface properties for reduced adhesive andelectrostatic forces in order to facilitate the breaking apart ofsettled or aggregated particles prior to and during dispense. Further,micro and nano particle formulations of drugs are often employed usingbiocompatible and degradable polymers as carriers.

All of these and other powder engineering principles play an importantrole in conjunction with the design of packaging and dispensing devicesto achieve precise delivery of powdered drugs. A variety of packagingand devices are known for delivering a controlled quantity of a drypharmaceutical preparation to the nose, nasal mucosa, sublingual,buccal, oral mucosa, pharyngeal, tracheal, and lower respiratorytissues.

Unlike liquid drug formulations, whereby a simple pump can deliver aprecisely controlled quantity of drug as droplets with the requiredspray characteristics; drugs formulated as dry materials presentadditional challenges owing to the propensity of powders to settle andphysically and chemically agglomerate. Thus it is necessary that thedevice must not only contain a single dose of material or be capable ofmetering it from a bulk source, but must also impart sufficient energyto agitate the material to break up the particles and propel them to theuser in the correct quantity and mean particle size in order to provideoptimum deposition characteristics, and consequently the mostadvantageous therapeutic effect.

There exists numerous means and devices to dispense powders to a user;the basic designs of which vary depending upon the site ofadministration and the target deposition zone within the respiratorytract. For example, Dry Powder Inhalers (DPIs) is the class of devicesthat is perhaps the most common type of device for delivering drypharmaceutical preparations to a user most typically for pulmonarydeposition via oral administration. Typically such devices require anexternal propellant, pressurizer or other external energy source whichclassified those devices generally as Active Dry Powder Inhalers(ADPIs). Alternatively, other devices rely solely on the inspiratoryairflow of the user and hence are breath actuated and referred to asPassive Dry Powder Inhalers (PDPIs). Both approaches suffer fromsignificant drawbacks. In the case of ADPIs, owing to the need for apropellant or electromechanical componentry and often bulk storage ofdrug; the device itself can be complex, large, expensive, cumbersome,and inconvenient to handle and use. Passive devices while often smaller,less expensive and containing one or more individualized unit doses;often deliver inconsistent quantity of drug to the user with thevariability of delivered dose a function of user inspiratory flowrate.Further, the passive devices often operate at a reduced efficiency asgiven by the fraction of the dose quantity actually delivered to theuser. The reduced efficiency diminishes the cost effectiveness of thepassive devices due to wasted drug material. The undispensed portion ofthe drug that remains is also left behind to contaminate the device, andin the case of multi-dose devices, possibly contaminate subsequent dosesof drug.

In the case of pulmonary deposition, very small particles (1-5 microns)are preferred but smaller particles typically suffer from an increasedtendency to form clumps due to hygroscopicity, adhesive andelectrostatic forces. Prior art devices commonly rely on high velocitypropellants or electromechanical agitation to de-aggregate the powderparticles and deliver the material to the target deposition zone of theuser. The means of providing the external energy source are widelyvaried and include pressurized canisters, propeller type agitators,mechanical, solenoid or piezoelectric based vibration to aid in particledeaggregation and delivery. For example, Gumaste in U.S. Pat. No.7,950,390 discloses a microelectronic piezo vibrator to aid breakingapart the agglomerated particles and suspending them into the flowfield. Such microelectronic systems offer improvements in the bulk sizeof the device as compared to Wilke et al, who in U.S. Pat. No. 3,948,264discloses a battery driven electro-mechanical vibrator to facilitatedispersion and release of the particles. These schemes, whileincrementally different, consistently suffer from the disadvantage ofsystem complexity due to the need for circuitry, motors, and electricalpower sourcing. Additionally, these prior art types of devices oftenentail capsule based dosage forms externally pierced by various meansoften including retractable mechanical or motor driven pins, oftenarranged in multiple pin arrays and channels to facilitate increasingthe fraction ejected from the dosage form.

Alternatively, passive devices rely upon the forceful inhalation of theuser to disperse the particles and deliver them to the airway and thetargeted tissues. In most prior art, active and passive devices, theoperation often entails a series of steps to facilitate administrationof drug. Additionally, the dosage forms are often singulated in the formof capsules containing the prescribed dose quantity that must first beexternally pierced in order to expose the compound to the velocityfield. The other dosage form common in such devices are individualblisters either singulated or in strips or cartridges that are loadedinto the dispensing device and also first require either piercing of theblister or peeling of the upper lidding layer to expose the contents.For example, Davies et al in U.S. Pat. Nos. 5,590,645; 5,860,419;5,873,360; 6,032,666 discloses an inhalation device with a multi-dosageconfiguration in the form of a strip of individual blisters containingthe medicament. The base and lid materials are peeled apart as the stripis rotated into an opening station position and the two ends taken up onseparate spools. Once in position and the contents exposed, the userthen inhales the drug compound. This prior art device has the advantageof simplicity owing to the reliance upon the users inhalation as theprimary means of particle dispersion and delivery. However, thatapproach may result in poor dose consistency; as measured by patient topatient variability or dose to dose variability of an individualpatient. This variability is a consequence of the natural range ofpossible patient inspiratory rates and velocities. Further, the passivescheme as disclosed whereby no means are provided to augment theejection of the blisters, may result in incomplete dosing and lowefficiency of delivery whereby medication is left in the blister.Further, the undelivered quantity continues to reside within the openedblister and once indexed may fall out into the device interior,contaminating both the device and possibly subsequent doses.

Often such prior art devices incorporate various aspects on the exteriorof the dosage form or in the device itself such as channels, variouslyconfigured inlets, outlets, and orifices or other turbulence promotingmeans for improving the dispersion of the particles. However, most suchschemes result in modest improvement in dose efficiency.

The present invention addresses these disadvantages in the prior artdevices by providing for a dosage form that is internally pierced usingthe user's own force. The internal piercing mechanism also providesagitation and pressurization of the blister form to impart velocity tothe particles to break apart settled and agglomerated material andproduce an inspiratory flowrate independent dosing. The combined dosageform and device can be single or multi dose capable for either nasal ororal administration of a range of particle sizes. The dosage and deviceprovides for improved patient ease of use owing to its compact size andsimple design without the need for electrical circuits or power sources,low cost, and consistent, contamination free dosing of dry powder drugcompounds.

Device technology has lagged current powder formulation and powderengineering capabilities such that the enhanced precision andeffectiveness of new and existing powdered drugs can be fully harnessed.The present disclosure provides dosage forms with integrated dispenseenergetics for delivery of predetermined quantities of dry powder orgranular pharmaceutical or medical compositions for local and/orsystemic action. Integrating the device energetics into the dosage formreduces overall device cost, complexity, and bulk to improve patientcompliance and ease of use.

SUMMARY OF THE INVENTION

The present invention provides dosage forms with internal componentrywhich provides for piercing or opening of the form from the inside,mechanical agitation of the drug contents, and to aid in dispersion anddispensing of the drug to a user. The dosage forms may be in certainembodiments a biologic, a biological agent, or a small or large moleculepharmaceutical drug compound. The drug dosage forms are for use indelivery devices that deliver the drug compound as a dry powder,particles, granules or other agent or formulation as a dry material to ahuman or non-human animal. The dosage forms can be used, for example, todeliver one or more measured doses of a dry pharmaceutical, biologic ormedical composition to the nose, nasal passages, mouth, throat, trachea,pharynx, upper or lower airways to include into the lungs, or to atopical location of a user for the therapeutic or prophylactic treatmentof local or systemic conditions.

Any powder or dry form pharmaceutical is contemplated in the presentdisclosure, including but not limited to antibiotics, antipyretics,anti-inflammatories, biologics, vitamins, co-factors, enzymes,inhibitors, activators, nutrients, aptamers, thioaptamers, vaccinesincluding killed or live virus or microorganisms, nucleic acids,proteins, peptides, antibodies, peptide mimetics, micro ornanoparticles, or other agents known in the art. The following is alimited list of examples of general classes of pulmonary drugsadministered as inhalable dry powders for a host of indications whichcan include but not limited to anemia, asthma, bronchitis, cancer,cystic fibrosis, diabetes, osteoporosis, hepatitis, arthritis, chronicor acute pain, immunodeficiency disorders, multiple sclerosis,endocrinological disorders, etc. Drug compounds for treating thoseindications include, various adjuvants, calcitonin, erythropoietin,heparin, inhibitors, insulin, interferons, interleukins, hormones,neurotropic agents, growth factors, stimulating factors, vasodilatorsand constrictors, etc. This list is not intended to be exhaustive and inno way is inclusive of all possible conditions and diseases, drugs andcompounds, or routes or targets of administration, but rather is toillustrate the breadth of dry powder drugs and indications employable inthe present invention and contemplated by the present disclosure.

In certain embodiments, the medical compositions are in the form apowder, or a dry pharmaceutical combined with one or more active agentsand combinations of pharmaceutically acceptable carriers or materials toinclude matrix agents, diluents, preservatives, coatings, adsorption orabsorption enhancing or delaying agents, salts, bulking or fillingagents, anti-clumping agents, adjuvants, buffers, chelators, or otherexcipient ingredients known to those in the art as needed to affect thedrug's stability, flowability, adhesion, dispersion and deaggregationcharacteristics, or pharmacological uptake, efficacy, activity and rateof release. For example, in certain embodiments a predetermined quantityof biological or pharmaceutical material may be combined with mannose,lactose or other carrier or bulking agents known in the art. The drugmay also be bound to or encapsulated within nanoparticles or othermacromolecules to aid in stabilizing the drug and/or affecting the drugcompound's rate of release over time. Any conventional media or agentcompatible with the active agent is contemplated. More than one activeagent may also be incorporated into the compositions, for the same orseparate purposes. The phrase “pharmaceutically acceptable” refers tocompounds and compositions that are appropriate for human or non-humananimal use and do not otherwise produce an allergic or other undesiredreaction or effect when administered to a human or animal.

The present disclosure addresses the inherent disadvantages of prior artdry powder delivery dosage forms and devices. The present inventionprovides crushable dosage forms that contain the dry powder as well asan internal piercing device that opens the dosage form and agitates thedrug to break apart the particles and disperse them to the user. Variousdevices within the prior art include measured quantities of dry powderedformulations and pharmaceutical compositions contained in a crushableampoule, blister or other dosage form that entail forcing the formagainst an eternal piercing device during use, in order to pierce thedosage form and release the contents. The inherent disadvantages involvethe reliance on external energy sources and/or solely upon theinhalation force of the user to adequately break apart the settled andaggregated dose material into individual particles. The presentinvention provides for piercing the dosage form from the inside wherebythat piercing device and piercing event agitate the form contents tobreak up the material, and deliver the dry powder to the user. In thepresent invention, the energy source for particle break up, dispersion,and delivery is provided by the user's hand force during the mechanicalactuation of the device. In certain embodiments the user driven deviceactuation force may be combined with or augmented by additional externalenergy supplying means and devices and contemplated herein.

In certain embodiments the crushable unit dosage forms of the presentdisclosure are blisters that can be manufactured as described by Nelsonin U.S. Pat. No. 7,963,089 and incorporated in its entirety herein byreference. The manufacturing processes for forming blister wells forunit-dose packaging in a continuous web can include a step of drawing ametal, polymer, or laminated metal-polymer foil or other suitable sheetof material with the appropriate mechanical characteristics to allow hotor cold forming and drawing known in the art. In certain embodiments,one or more plungers can be used to form a primary contour, the contourhaving a depth of at least 100% and up to 150% of the depth of the finalformed recess or well. A second stage involves shaping the primarycontour with one or more of the same or additional plunger(s) to thedesired formed recess depth and shape, with a depth that is less thanthe depth of the primary contour, while substantially maintaining thesurface area of the primary contour formed in the first stage. Thecontour or shape of the blister well can be formed to contain certainshape features, indentations, or be imparted with texture by the formingpins to provide for a means of securing the internal piercing devicewithin the blister well or recess. The formed well or recess is thenloaded aseptically with the predetermined quantity of sterile dry powderand the internal piercing device and a lidding material of the same orsimilar laminated material as the blister well or other sheetingmaterial can be rolled atop the recesses and bonded to the well sheetingwith adhesives, or by thermal or ultrasonic or other welding means. Themass and volume of particles dispensed from an individual blister arevarious depending upon the blister shape and volume, the required volumeof headspace gas, and the powder characteristics, which are primarilythe bulk density which is affected by the particle shape, size, andadhesion and aggregation properties, among others. For example, thedosage mass and volume for intranasal or orally administered pulmonarytreatments can range from 1 to 50 milligrams and 10 to 100 microliters,respectively. This is but a single typical range for one application;ranges for other indications and routes of administration and neededtherapeutic quantities can vary substantially and are contemplatedherein to include ranges to gram level masses and 1000 microliters dosevolume or more for certain topical administered compounds.

In certain embodiments, the individual blisters that can be formed insheets are in later manufacturing steps, singulated into single dosesfor use in single-use, disposable, non-reloadable devices, or for use indevices which are reloadable with additional unit doses for subsequentdosing of the same or different patient(s). Alternatively, and dependingupon the application and indication, the sheets may be formed and cutinto rows, arrays, grids or other configurations of blisters suitablefor use in multi-dose devices. Regardless of the shape, size, orgeometric configuration of blisters, ampoules, or wells; each unitcontains an internal piercing element.

Preferred embodiments of the present invention can provide dosage formscontaining a piercing device that pierces the blister from the inside,mechanically agitates the dry powder, disperses, and dispenses theblister contents from the blister to the user.

The internal piercing device can include a lower section that is acircular ring, a disk, or has a concave shape, and a hollow tip that isan elongated member extending from the lower section. The ring can benarrow, flat or tubular in shape and stabilizes the internal piercingdevice's position within the blister. The device can include connectingmember splines, spokes, ribs of various shapes and numbers to connectthe stabilizing ring to the hollow tip in order to provide forcommunication of the blister contents to the hollow tip's internalchannel for dispensation of the powder. The hollow elongated tip caninclude additional orifices, channels, obstructions or other structuralfeatures to affect agitation and turbulent flow within the blisterand/or within the tip during piercing and dispensing of the dry powder.

In preferred embodiments, two, three or a plurality of the connectinglegs or members can connect the ring element to the hollow elongatedtip; the legs of which can be flat, circular, or curved or arch shaped;such that they form a substantially vacant interior cavity for thepowder to reside and divide the powder to reduce caking and aid indispersion.

In certain other embodiments, the base and leg members can be a mesh orporous material or a highly perforated disk that provides void spacesfor deaggregation and to prevent or reduce caking or settling of thepowder and to promote turbulence to aid in powder dispersion duringdispense.

In certain embodiments, the hollow elongated tip can be of variousshapes to include but limited to a parallel walled pipe to a taperedhollow cone. The internal channel can be of constant diameter, tapered,rifled or containing other structures to affect velocity, pressure, andturbulence. The inside diameter of the hollow elongated tip can rangefrom about 0.01 to 0.1 inches depending upon the powder characteristicsand puncture needs. For example, for a powder that is free flowing witha small mean diameter, with low homogeneous adhesivity, and low dosemass; where a quick, short puncture event is preferred, a thicker walledtip will better support a sharper tip, which hence permits a smallerinterior diameter of the tip.

The total height of the internal device including the base and hollowelongated member is less than the internal height of the blister well atits center, but in certain other embodiments may be of slightly greaterlength to include the range of 110% or more of the inside height of theblister to provide for pre-stretching or pre-puncturing of the lidstock.The hollow tip end can be of blunt to sharp shape to facilitate or delaythe piercing of the blister lidstock during the crush event to providefor variable internal pressurization prior to blister dispense to impartagitation and aid in deaggregation and dispersion. In summary, theinternal piercing device's elongated tip, base and connecting legmembers act in conjunction to divide the powder dose, promote turbulentmixing, and pressurization prior to and during dispensation of thepowder from the blister.

In certain other embodiments, the piercing device can be describedwherein the legs, splines, or spokes that connect the base section tothe elongated hollow tip can be made thin such that when the blister isundergoing crushing, the piercing device collapses whereby the elongatedtip moves downward and the base ring flips forward such that it acts asa mechanical spring the energy of which acts to provide agitation anddeaggregation of the powder material.

In certain embodiments, therefore, the disclosure may also be describedas a piercing device that acts to agitate and dispensing a predeterminedquantity of solid composition from a dosage form. The piercing deviceincludes an elongated hollow tip member with an inlet end and adischarge end, with the internal channel connecting the inlet end andthe discharge end in fluid communication, a blunt or sharp shaped tipforming a discharge opening in the discharge end, and features on theinternal chamber surface to control the pattern of powder forced throughthe piercing device such that it also acts as a nozzle. The disclosureincludes, therefore, a dosage form that comprises the piercing deviceand a quantity of a dry powder pharmaceutical composition.

The internal piercing can be manufactured by techniques known by thoseskilled in the art, for example injection molding or machining. Thepiercing device can be constructed of any material with suitablechemical compatibility and mechanical properties to impart the designedfor strength characteristics such as ceramic, glass, metal, plastics andin preferred embodiments, can be constructed from polymeric materials toinclude but not limited to polyethylene (PET), polypropylene,polystyrene, or poly ether ether ketone (PEEK), self-reinforcedpolyphenylene (SRP) or other pharmaceutical or medical grade materials.In preferred embodiments, the internal piercing devices are injectionmolded as single piece components, however in certain other embodimentswhere certain structural features are less amenable to one piecemolding; the devices can be assembled from multiple machined and/ormolded parts. For example, certain embodiments may entail attaching bysnap or press fit or threading of a machined metal elongated tip to aplastic base part. Other combinations of parts, manufacturing methods,materials, and assembly methods are well known in the art and fullycontemplated herein.

In certain preferred embodiments the present disclosure is a dosage fromcontaining an internal piercing device as described herein. The dosageform can be a crushable blister or ampoule containing a powder medicalcomposition. The blister well can be sized to permit sufficient volumeto contain both the prescribed dose quantity of dry powder materialloaded into the blister as well as a headspace of free gas volume thatremains to permit pressurization and agitation of the contents. Suchdosage forms are for use in delivery devices and systems in which ahandheld device that includes an actuation mechanism that can include aram, piston or plunger which when forced against the dosage formpressurizes the blister contents during the compression phase of thedispense that occurs prior to and during initial breaching or piercingof the lidstock by the internal piercing device. Once pierced, thepressurized and agitated contents are forced out through piercingdevice's elongated hollow tip internal channel.

The present disclosure provides a dosage form containing dry powdermedical composition and an internal piercing device that provides theadvantages of pressurization, agitation, dispersion integral to theblister owing to the internal piercing device which also acts as anozzle to dispense the powder contents to the user without therequirement of an external energy source common with active devicesknown in the art and provides increased ejection fraction and hencegreater efficiency of drug delivery above that as provided by passivedevices.

Throughout this disclosure, unless the context dictates otherwise, theword “comprise” or variations such as “comprises” or “comprising,” isunderstood to mean “includes, but is not limited to” such that otherelements that are not explicitly mentioned may also be included.Further, unless the context dictates otherwise, use of the term “a” or“the” may mean a singular object or element, or it may mean a plurality,or one or more of such objects or elements.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areintended to further demonstrate certain aspects and embodiments of thepresent invention. Reference to the drawings in combination with thedetailed description is intended to further illustrate certain featuresof the internal piercing device in conjunction with the dry powdercontaining dosage form.

FIG. 1 a is an embodiment showing a cutaway view of a unit dosage formof the present invention containing an internal piercing device withsupport members forming a cage-like structure and substantially freeflow path.

FIG. 1 b is the same embodiment showing a top view of a unit dosage formof the present invention containing an internal piercing device.

FIG. 2 is an embodiment of a dosage form with a high internal volumevoid cavity formed by three spokes or connecting members between thering and hollow elongated tip.

FIG. 3 is an embodiment of a dosage form with a mesh or highly porousbase internal piercing device.

FIG. 4 is an embodiment of a dosage form with an internal piercingdevice with a tip modified to facilitate puncturing or piercing of thelidstock.

FIG. 5A is an embodiment of a dosage form with an internal piercingdevice that is collapsible and acts as a mechanical energy storagedevice that springs forward to aid in powder agitation and breakup.

FIG. 5B is a view that shows the collapsed piercing device.

FIG. 6 is a view of a dosage form with internal piercing device loadedwith dry powder.

FIG. 7 demonstrates a dosage form during the pressurization phase.

FIG. 8 demonstrates a dosage form during the piercing phase.

FIG. 9 demonstrates a dosage form during the agitation and break upphase.

FIG. 10 demonstrates a dosage form during the dispense phase.

DETAILED DESCRIPTION of the PRESENT INVENTION

Preferred embodiments of the present disclosure provide dosage formsthat contain a measured quantity of dry powder, a piercable section suchthat the dosage form can be pierced, an internal piercing device thatpierces the piercable section, provides agitation and dispersion of thepowder and communicates the powder to a user. When employed in a typicaldevice, a plunger, lever, ram, wheel, or some other mechanical devicecontacts the dosage form with sufficient force to crush the dosage formto expel the powder contents out of the pierced opening. The dosage formcan be generated using methods well known to those of skill in the art,including, for example, form fill seal technology or blow fill sealtechnology, or by deep draw forming as described in U.S. ApplicationPublication No. 2009/0071108, incorporated herein in its entirety. Theform-fill-seal process can be used to create a blister, for example apack or strip of blisters, from rolls of flat sheet or film, filled withthe dry powder pharmaceutically active agent, and closed or sealed onthe same equipment. This process entails clamping the laminate or filmmaterial, pressing one or more forming pins through plates withappropriately sized and spaced openings to form the blister well orreceptacle in which the pharmaceutically active agent, or an agent thatmay be mixed or combined with a pharmaceutically active agent is placed.The lidstock or lidding of the same or similar material is sealed acrossthe blister well leaving a pierceable covering through which the agentis dispensed out of the blister.

Preferred embodiments of the present disclosure provide dosage forms foruse in delivery devices for intranasal or oral administration of drypowder drugs or pharmaceutical compositions. A controlled quantity ofdry material is contained in a blister form that also contains aninternal piercing device. One or more sealed unit dose blisters are thenloaded or mounted into a handheld device that allows a user to dispensethe powder. When the blister is mechanically compressed or crushed bythe device, the internal piercing device ruptures the blister, agitatesand disperses the powder contents and provides a channel for theexpulsion of the powder into the nose or mouth of a user.

FIG. 1A is a cutaway view of an example of a dosage form. The blisterwell or receptacle 10 is sealed by the lidding or lidstock material 11to form a single unit dose blister. Contained within the closed blisteris an internal piercing device with a base ring 12. Multiple supportmembers 13 communicate with the hollow elongated tip 14. The channelsform a substantially open, conical shaped volume 15 within the piercingdevice. The void volume is designed to promote free flow of the powderto the tip. The tip can be have tapered or straight walls 16, can besubstantially smooth internally or contain structural features to aid inpowder breakup, and can be blunt or sharp at the end 17 to facilitate ordelay puncture. During dispense, the opening at the tip end 18 forms thedischarge point for the powder which is delivered to the user.

FIG. 1B is a top down view of the same dosage form shown in FIG. 1A. Inthis view, the ring 12, support members 13, elongated tip 14, and thedischarge opening 18 diameter are evident.

As discussed in the background section, those skilled in the art arefamiliar with the range of factors affecting the flow characteristics ofdry powders as well as the powder engineering and formulation principlesentailed in achieving a free flowing powder. The quantity of dry powderpharmaceutical contained in a dosage form nonetheless can settle, cake,and aggregate. The internal piercing devices as shown in FIG. 1A, 1B andFIG. 2A, 2B are designed to provide a high volume flow path for thepowder. Rather than individual orifices and small channels, which in thecase of powder dispensation would otherwise tend to plug or clog, thepresent invention provides embodiments that have a stabilizing ring 12with several connecting legs or members 13 that connect the ring to thehollow elongated tip 14 thus providing a substantially freer or cleanerpathway for the powder to travel. In the various configurations, theconnecting members can be, for example, arched to provide a concavecenter volume space 15 that gives a substantially open flow path forpowder. Additionally, the number of connecting members can be few, e.g.one to three; or several, e.g. four or more, to divide the powder intoindividual segments within the blister during storage. During dispense,the individual segments of powder serve to break apart the powder thusproviding for greater powder surface area exposure to the pressure thatoccurs during blister compression; further breaking apart the powdercake and propelling it into the piercer hollow elongated tip fordischarge.

For even greater division of the powder dose contained within a dosageform, the internal piercing device embodiment of FIG. 3 provides a meshor highly porous base 19. The base can be disk shaped or concave andattached to the elongated tip 14. In the case of a mesh base, theirregular segments of powder 20 act to increase turbulence in thepressure field acting upon the powder during blister compression anddispense.

FIG. 4 is an embodiment demonstrating a tip modified to facilitate thepiercing of the lidstock. The height of the elongated tip 14 and itsbluntness or sharpness, the blister headspace volume 21, and lidstocktensile strength due to its composition and thickness combine to dictatethe time and distance of travel that occurs during blister crushingbefore the piercing event occurs. These design parameters allow foroptimization of the pressure to increase agitation, dispersion andvelocity of the powder at discharge. Integral to blister pressurizationis the smooth exterior wall 22 of the tip that provides a seal betweenthe tip and the lidstock opening during piercing and discharge. The sealis advantageous to maintain the blister pressure and assure the powderis ejected through the tip's internal channel 18.

An embodiment of internal piercing device is shown in FIGS. 5A and 5Bwhereby the legs 13 or members connecting a ring base 12 to the hollowelongated tip 14 are designed with a narrowed section 23 such thatduring blister crush and prior to piercing, the tip collapses into thedisk. The arched connecting members invert themselves which snaps thelower ring forward or upward (FIG. 5B). In this embodiment, the internalpiercing device acts as a mechanical energy storage device that impartsenergy into the dosage form prior to and during dispense to agitate anddisperse the powder.

There are multiple stages involved in a typical powder dispense from adosage form. They can be generally described as phases, all of whichinteract and can overlap one another. They start with an actuation by aforce external to the blister acting upon a rod, cam, lever, or othermeans, mechanical or electromechanical, known in the art, to result incrushing of the blister form, which causes a pressurization of thesealed dosage form, which promotes the agitation and breakup of thepowder. This phase overlaps substantially with the piercing phase,whereby the internal piercing device is moved forward or upward duringcrushing and punctures or pierces the lidstock from the inside. Oncepierced, the pressure equalization and dispense phases begin.

FIGS. 6-10 illustrates the sequence of dispense phases. FIG. 6 shows ablister dosage form containing the internal piercing device as waspreviously shown in FIG. 3 loaded with powder 24 as stored. FIG. 7 showsthe dosage form loaded into a dispensing device. As the plunger 25compresses the blister, the piercing device stretches the lidstock 11prior to piercing. FIG. 7 shows the unit dose blister duringpressurization, which occurs up to the point of first fissure of thelidstock 11. The emerging hollow elongated tip 14 then protrudes intothe device opening 26. Once fissure of the lidstock occurs 27, FIG. 8,the blister contents 24 are exposed to a pressure gradient between theblister interior and the outside ambient pressure. As the pressuregradient seeks to equilibrate, the turbulent forces within the blisteract upon the powder and the piercing device's connecting members whichimpart irregular velocity vectors to agitate, break up, and disperse thepowder 24 (FIG. 9). With the powder broken up by the agitation acting inconjunction with the connecting members 13, the free flowing powder ispropelled into the center channel 18 of the elongated hollow tip 14 andexits the blister and delivered to the user, as shown in FIG. 10.

When the dose is to be administered, the dosage form is placed in adevice designed to administer the pharmaceutical agent to a particularlocation, such as in the eye, ear, nose, mouth, lungs or skin of a user,for example. The device may administer the pharmaceutical agent throughoral, peroral, enteral, parenteral, pulmonary, rectal, otic, topical,nasal, vaginal, lingual, direct injection, intravenous, intraarterial,intracardial, intradermal, intramuscular, intraperitoneal,intracutaneous, intraocular, ophthalmic, intranasal, intrapleural,intrathecal, intratumor, intrauterine, orthotopic, transdermal, buccal,and subcutaneous or other routes of delivery. Many such devices includea firing mechanism that drives a ram against the dosage form with anexplosive or incremental force. Examples of such devices are describedin pending U.S. Application Publication No. 2008/0177246, incorporatedherein in its entirety by reference. In certain embodiments in using thedosage forms of the present invention containing the internal piercingdevice, the energy input is the result of the hand force supplied by theuser. Though additional external energy sources and mechanisms arecontemplated herein, the present disclosure provides a device whichresults in powder agitation and dispersion that occur from internalblister forces provided by the internal piercing device acting inconjunction with the blister pressurization. Said pressurization can inpreferred embodiments occur from hand forces supplied to the device bythe user. Therefore as compared to existing devices which are generallyclassified as either active or passive, the present invention is ahybrid of the two whereby the energy required to disperse and deliverthe powder to a user is accomplished as a result of the work inputprovided by the device user and can be augmented by user inspiratoryairflow.

Typically, a user administers a dry powder orally, intranasally ortopically via a hand levered device that contains one or more dosageforms of the present invention. It is an advantage of the presentdisclosure that the dosage form can be incorporated into a multitude ofdevices and configurations. Further, the internal piercing devices anddosage forms can operate independent of orientation, eitherhorizontally, vertically, or at an angle.

All of the devices and methods disclosed and claimed herein can be madeand executed without undue experimentation in light of the presentdisclosure. While the devices and methods of this invention have beendescribed in terms of preferred embodiments, it will be apparent tothose of skill in the art that variations may be applied to the devicesand/or methods and in the steps or in the sequence of steps of themethods described herein without departing from the concept, spirit andscope of the invention. All such similar substitutes and modificationsapparent to those skilled in the art are deemed to be within the spirit,scope and concept of the invention as defined by the appended claims.

1. A piercing device internal to a dosage form for dispensing apredetermined quantity of dry powder to a user, said device comprising:a ring; a hollow elongated member comprising an internal channel and apiercing tip; one or more legs or members providing support to thehollow elongated member and connecting it to the ring wherein a fluidpath is formed to allow communication of the dosage form contents intothe hollow elongated member.
 2. The piercing device of claim 1 furthercomprising a tip that is angled or shaped to provide a sharp pointeffective to adjust the piercing time, distance, or degree of stretchingof the blister form lidding material.
 3. The piercing device of claim 1further comprising an elongated hollow member with internalrestrictions, steps, flutes, ribs or other structural features to affectthe breakup, dispersion, or spray pattern of the powder during dispense.4. The piercing device of claim 1, wherein the support members areshaped as substantially flat elements or ribs.
 5. The piercing device ofclaim 1, wherein the support members are curved, angled, or archedeffective to form a substantially conical or concave shape region at thebase of the hollow elongated tip.
 6. The piercing device of claim 1,wherein the support members have thin, narrowed, scored, or pinchedsections, or otherwise designed such that the piercing device bends,springs, vibrates or collapses during crushing of the blister to affecta mechanical release of energy prior to and/or during dispense.
 7. Thepiercing device of claim 1, wherein the elongated hollow tip is incommunication with a mesh or porous base.
 8. The piercing device ofclaim 1, wherein the support members support and stabilize the hollowelongated member within the dosage form without use of a ring.
 9. Adosage form containing an internal piercing device of claim 1 and acomposition formulated as a dry powder for administration to a human ornonhuman animal.
 10. A dosage form containing an internal piercingdevice of claim 1, a predetermined quantity of dry powder and one ormore inlet channels for the introduction of a liquid quantity forresuspending or converting the powder to a solution or suspension priorto administration to a user.
 11. A device for dispensing a predeterminedquantity of dry powder to a user, comprising: a body comprising a nozzleend designed for insertion into a nostril of a user; a trigger device; adosage form comprising a crushable ampoule or blister comprising aninternal volume, a pierceable membrane and containing the powder and thepiercing mechanism within the internal volume; wherein the internalpiercing device comprises a ring, an elongated hollow tip, and one ormore legs or members connecting to and providing support to said hollowelongated member that also forms a discharge channel and nozzle; anactuator in contact with the trigger device; a plunger connected to theactuator; and wherein operating the trigger causes the plunger to crushthe dosage form and the piercing device to penetrate the pierceablemembrane and discharge the powder through the discharge channel; andfurther wherein the actuator modifies a mechanical force applied fromthe trigger device to the plunger.
 12. The device of claim 10 furthercomprising a tip that is angled or shaped to provide a sharp pointeffective to adjust the piercing time, distance, or degree of stretchingof the blister form lidding material.
 13. The device of claim 10 whereinthe internal piercing device further comprises an elongated hollowmember with internal restrictions, steps, flutes, ribs or otherstructural features to affect the breakup, dispersion, or spray patternof the powder during dispense.
 14. The device of claim 10, wherein theinternal piercing device further comprises support members that areshaped as substantially flat elements or ribs.
 15. The device of claim10, wherein the internal piercing device further comprises supportmembers that are curved, angled, or arched effective to form asubstantially conical or concave shaped region at the base of the hollowelongated tip.
 16. The device of claim 10, wherein the internal piercingdevice further comprises support members that have thin, narrowed,scored, or pinched sections, or otherwise designed such that thepiercing device bends, springs, vibrates or collapses during crushing ofthe blister to affect a mechanical release of energy prior to and/orduring dispense.
 17. The device of claim 10, wherein the internalpiercing device further comprises an elongated hollow tip incommunication with a mesh or porous base.
 18. A dosage form containingan internal piercing device of claim 1, a predetermined quantity of drypowder and one or more inlet channels for the introduction of a liquidquantity for resuspending or converting the powder to a solution orsuspension prior to administration to a user.
 19. The device of claim 10further comprising electrically driven triggering and actuation means toinclude solenoids, motors, piezoelectric elements or otherelectromechanical methods and devices for crushing the blister form. 20.The device of claim 10 further comprising electrically driven triggeringand actuation means to include solenoids, motors, pumps, propellers,fans, piezoelectric elements or other electromechanical methods anddevices for providing additional dispersion and propulsion of the powderdispensed from the dosage form to the user.